We have shown that testosterone increases the activities of lysosmal and mitochondrial enzymes in a number of extragential tissues in mouse and rat, including heart, skeletal muscle and kidney; and that these tissues display a sex difference in lysosomal and mitochondrial enzyme activities that is mediated by endogenous androgens. In mouse kidney, testosterone was found to induce early (5-20 min) activation of the lysosomal system, and a modification in mitochondrial structure, whereas orchiectomy had the obverse effect. Further, testosterone enhances the cardiac and aorta hypertrophy induced by the beta-adrenergic agonist isoproterenol. On the basis of our studies, we propose a two-stage model of androgenic hormone action in the heart. In the first stage, testosterone binds to specific cell surface receptors and initiates a cascade of membrane reactions involving sequential increases in Ca2+ influx, prostaglandin synthesis and cAMP levels, and leads to a cAMP-dependent surge of ornithine decarboxylase (ODC) activity, possibly by phosphorylation of an inactive enzyme. The resultant rise in polyamines initiates the second stage with an RNA-dependent de novo synthesis of ODC and a sustained increase in polyamines which, possibly in concert with nuclear androgen-receptor complexes, enhance pinocytosis, autophagy and lysosomal activity, stimulate synthesis of lysosomal enzymes and cytochrome c oxidase, augment RNA and protein synthesis and induce growth. The polyamines serve as an intracellular signal to turn on and sustain these and other Ca2+-mediated processes by binding to calcium storage depots and releasing Ca2+ into the cytoplasm. Androgens could modulate the beta-adrenergic receptor activity (receptor numbers or affinity). The purpose of this research project is to further characterize the metabolic effects of testosterone, to elucidate the mechanism of androgenic action in the rodent heart, and to test the validity of this model.